PROJECT SUMMARY/ABSTRACT Spinocerebellar ataxia type 1 (SCA1) is a devastating neurodegenerative disease characterized by progressive ataxia from cerebellar degeneration. Death typically occurs by the third to sixth decade of life. While the hallmark of SCA1 is loss of motor coordination or ataxia, at the end stage of disease premature death results from complications secondary to bulbar dysfunction, including swallowing difficulties and breathing dysfunction. In SCA1, disease is caused by expansion of CAG repeats encoding poly-glutamine (polyQ) in ATAXIN1 (Atxn1). Substantial effort has been invested in determining the molecular mechanism leading to cerebellar degeneration, specifically Purkinje cell death, from polyQ expanded Atxn1. This is largely due to the fact that Purkinje cells seem to be the first neurons affected in SCA1 and they are most vulnerable to the pathogenic sequelae of expanded polyQ Atxn1. However, loss of Purkinje cells does not account for the bulbar dysfunction phenotype, which ultimately causes premature death. I hypothesize that motor neuron degeneration is responsible for bulbar dysfunction in SCA1. Further supporting this hypothesis is SCA1 autopsy data showing marked loss of motor neurons in the brainstem. In 2002 our lab developed a pivotal mouse model for SCA1 recapitulating the major human features of disease with robust face and construct validity. In this model, designated Atxn1-154Q, 154 CAG repeats were knocked into the endogenous mouse Atxn1 gene locus. Upon joining the Zoghbi lab, with my clinical expertise in neuromuscular diseases, I made the exciting observation that these mice display overt signs of motor neuron degeneration. In particular I noted significant muscle wasting, breathing abnormalities and spasticity by 24 weeks of age. The goals of this proposal are to examine motor neurons in Atxn1-154Q mice functionally, morphologically and molecularly in order to better understand what causes their degeneration and to establish these mice as an ideal model to study motor neuron degeneration in SCA1.